View source for 6gev


==Mineralocorticoid receptor in complex with (s)-13==
<StructureSection load='6gev' size='340' side='right'caption='[[6gev]], [[Resolution|resolution]] 1.54&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6gev]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6GEV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6GEV FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EWN:6-[[(3~{S})-7-fluoranyl-3-(2-methylpropyl)-2,3-dihydro-1,4-benzoxazin-4-yl]carbonyl]-4~{H}-1,4-benzoxazin-3-one'>EWN</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NR3C2, MCR, MLR ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), NCOA1, BHLHE74, SRC1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Histone_acetyltransferase Histone acetyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.1.48 2.3.1.48] </span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6gev FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6gev OCA], [http://pdbe.org/6gev PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6gev RCSB], [http://www.ebi.ac.uk/pdbsum/6gev PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6gev ProSAT]</span></td></tr>
</table>
== Disease ==
[[http://www.uniprot.org/uniprot/MCR_HUMAN MCR_HUMAN]] Defects in NR3C2 are a cause of pseudohypoaldosteronism 1, autosomal dominant (PHA1A) [MIM:[http://omim.org/entry/177735 177735]]. A salt wasting disease resulting from target organ unresponsiveness to mineralocorticoids. PHA1A is a mild form characterized by target organ defects confined to kidney. Patients may present with neonatal renal salt wasting with hyperkalaemic acidosis despite high aldosterone levels. These patients improve with age and usually become asymptomatic without treatment.<ref>PMID:9662404</ref> <ref>PMID:11134129</ref> <ref>PMID:12788847</ref> <ref>PMID:16954160</ref> <ref>PMID:16972228</ref>   Defects in NR3C2 are a cause of early-onset hypertension with severe exacerbation in pregnancy (EOHSEP) [MIM:[http://omim.org/entry/605115 605115]]. Inheritance is autosomal dominant. The disease is characterized by the onset of severe hypertension before the age of 20, and by suppression of aldosterone secretion.<ref>PMID:9662404</ref> <ref>PMID:15967794</ref> <ref>PMID:15908963</ref> <ref>PMID:10884226</ref>  [[http://www.uniprot.org/uniprot/NCOA1_HUMAN NCOA1_HUMAN]] Note=A chromosomal aberration involving NCOA1 is a cause of rhabdomyosarcoma. Translocation t(2;2)(q35;p23) with PAX3 generates the NCOA1-PAX3 oncogene consisting of the N-terminus part of PAX3 and the C-terminus part of NCOA1. The fusion protein acts as a transcriptional activator. Rhabdomyosarcoma is the most common soft tissue carcinoma in childhood, representing 5-8% of all malignancies in children. 
== Function ==
[[http://www.uniprot.org/uniprot/MCR_HUMAN MCR_HUMAN]] Receptor for both mineralocorticoids (MC) such as aldosterone and glucocorticoids (GC) such as corticosterone or cortisol. Binds to mineralocorticoid response elements (MRE) and transactivates target genes. The effect of MC is to increase ion and water transport and thus raise extracellular fluid volume and blood pressure and lower potassium levels.<ref>PMID:3037703</ref>  [[http://www.uniprot.org/uniprot/NCOA1_HUMAN NCOA1_HUMAN]] Nuclear receptor coactivator that directly binds nuclear receptors and stimulates the transcriptional activities in a hormone-dependent fashion. Involved in the coactivation of different nuclear receptors, such as for steroids (PGR, GR and ER), retinoids (RXRs), thyroid hormone (TRs) and prostanoids (PPARs). Also involved in coactivation mediated by STAT3, STAT5A, STAT5B and STAT6 transcription factors. Displays histone acetyltransferase activity toward H3 and H4; the relevance of such activity remains however unclear. Plays a central role in creating multisubunit coactivator complexes that act via remodeling of chromatin, and possibly acts by participating in both chromatin remodeling and recruitment of general transcription factors. Required with NCOA2 to control energy balance between white and brown adipose tissues. Required for mediating steroid hormone response. Isoform 2 has a higher thyroid hormone-dependent transactivation activity than isoform 1 and isoform 3.<ref>PMID:9427757</ref> <ref>PMID:7481822</ref> <ref>PMID:9223431</ref> <ref>PMID:9296499</ref> <ref>PMID:9223281</ref> <ref>PMID:10449719</ref> <ref>PMID:12954634</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The mechanism-based risk for hyperkalemia has limited the use of mineralocorticoid receptor antagonists (MRAs) like eplerenone in cardio-renal diseases. Here we describe the structure and property driven lead generation and optimization, which resulted in identification of MR modulators ( S)-1 and ( S)-33. Both compounds were partial MRAs but still demonstrated equally efficacious organ protection as eplerenone after four weeks treatment in uninephrectomized rats on high salt diet and aldosterone infusion. Importantly, and in sharp contrast to eplerenone, this was achieved without substantial changes to the urine Na(+)/K(+) ratio after acute treatment in rat, which predicts a reduced risk for hyperkalemia. This work led to selection of ( S)-1 (AZD9977) as the clinical candidate for treating MR-mediated cardio-renal diseases including CKD and HF. Based on our findings we propose an empirical model for prediction of compounds with low risk of affecting the urinary Na(+)/K(+) ratio in vivo.

Identification of Mineralocorticoid Receptor Modulators with Low Impact on Electrolyte Homeostasis but Maintained Organ Protection.,Granberg K, Yuan ZQ, Lindmark B, Edman K, Kajanus J, Hogner A, Malmgren M, O'Mahony G, Nordqvist A, Lindberg J, Tangefjord S, Kossenjans M, Lofberg C, Branalt J, Liu D, Selmi N, Nikitidis G, Nordberg P, Hayen A, Aagaard A, Hansson E, Hermansson M, Ivarsson I, Jansson Lofmark R, Karlsson U, Johansson U, William-Olsson L, Hartleib-Geschwindner J, Bamberg K J Med Chem. 2018 Dec 31. doi: 10.1021/acs.jmedchem.8b01523. PMID:30596500<ref>PMID:30596500</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6gev" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Histone acetyltransferase]]
[[Category: Human]]
[[Category: Large Structures]]
[[Category: Aagaard, A]]
[[Category: Edman, K]]
[[Category: Tangefjord, S]]
[[Category: Ligand complex]]
[[Category: Mineralocorticoid receptor]]
[[Category: Nuclear hormone receptor]]
[[Category: Peptide complex]]
[[Category: Signaling protein]]
[[Category: Steroid receptor]]
[[Category: Transcription]]